Taurine and Painful Diabetic Neuropathy Diabetic neuropathy (DN) commonly complicates diabetes and can lead to lower limb amputations. In diabetes, neuropathic pain reduces quality of life, contributes to depression, limits exercise and impairs metabolic control thereby contributing to excess cardiovascular risk. Currently there are no treatments for DN other than improved metabolic control and conventional treatment for painful neuropathy can be cardiotoxic and have low efficacy. The etiology of pain complicating diabetes is poorly understood but may result from dysfunction of pain signaling pathways at multiple levels including cutaneous nociceptors, afferent neurons and spinal and supraspinal pathways. Taurine is a ubiquitous a amino acid, which functions as an antioxidant, regulator of glucose sensitive signal transduction pathways and analgesic such that its depletion in diabetes may contribute to the development of DN and pain. We have identified taurine depletion in the peripheral nerve of diabetic rodents and shown that taurine repletion alleviates hyperalgesia and prevents nerve metabolic, vascular and functional deficits. This proposal extends these observations and aims to explore the ability of taurine treatment alone to decrease pain and in combination with D-L-a-lipoic acid to improve nerve structure and function in patients with DN. The overall hypothesis is that taurine depletion contributes to the development of painful DN. The rationale is based on: (a) evidence implicating oxidative stress, altered neuronal calcium signaling and neuronal hyperexcitability in the development of painful DN (b) the emerging role of taurine as an important endogenous antioxidant, calcium regulator, neurotrophin, modulator of neuronal hyperexcitability and analgesic and (c) our data implicating an important role for taurine depletion and oxidative stress in the pathogenesis of experimental DN. The experimental approach will be to utilize biochemical, electrophysiological and imaging techniques to test the following aims: 1. Determine whether neuropathic pain complicating diabetes can be ameliorated by therapy with taurine. 2. Determine whether nerve functional and structural deficits complicating diabetes can be ameliorated by combination therapy with taurine and D-L-a-Iipoic acid. These studies will test a novel mechanistically based therapeutic approach to a common disabling and often-refractory complication of diabetes.